Redox regulation in lifespan determination

Abstract

One of the major challenges that remain in the fields of aging and lifespan determination concerns the precise roles that reactive oxygen species (ROS) play in these processes. ROS, including superoxide and hydrogen peroxide, are constantly generated as byproducts of aerobic metabolism, as well as in response to endogenous and exogenous cues. While ROS accumulation and oxidative damage were long considered to constitute some of the main causes of age-associated decline, more recent studies reveal a signaling role in the aging process. In fact, accumulation of ROS, in a spatiotemporal manner, can trigger beneficial cellular responses that promote longevity and healthy aging. In this review, we discuss the importance of timing and compartmentalization of external and internal ROS perturbations in organismal lifespan and the role of redox regulated pathways.

Keywords: ROS; aging; lifespan; longevity pathways; redox signaling; stress.

Figure 1

ROS scavenging and signaling mechanisms. Shown are contributing redox enzymes with lifespan-promoting (yellow), ambiguous (red), no or unknown (blue) effects on lifespan. CAT, catalase; GPX, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GSSG, glutathione disulfide; PRX, peroxiredoxin; TRX, thioredoxin; TRXR, thioredoxin reductase.

Figure 2

Measurement of ROS and oxidation in vivo. Redox sensors report on the redox state of their reactive cysteines, depending on the endogenous GSH:GSSG redox couple or their reactivity against specific oxidants (A, B) (118, 119, 120, 121, 122, 126, 127, 129). Redox proteomics rely on alkyne probes that selectively label cysteine thiols. These probes can be used to globally profile changes in cysteine reactivity due to disulfide formation, which inhibits probe labeling. For example, peptides from different samples can be labeled with isotopically tagged probes (probe 1 or probe 2) and subjected to mass spec analysis to calculate the relative oxidation of individual cysteines within the proteome (C) (150). GSH, glutathione; GSSG, glutathione disulfide; GRX1, glutaredoxin; ORP1, oxidant receptor peroxidase 1; OxyR, oxidative stress regulator.

Figure 3

Key modulators and targets of ROS that impact lifespan. The solid lines indicate known and direct interaction, transition, or ROS production; the broken arrows indicate mechanisms requiring further investigation. Shown are ROS sources (red) and scavengers (blue), redox relays (purple), redox-sensitive targets (green), and other associated proteins (orange). AMPK, AMP-activated protein kinase; CI, complex I in mitochondrial electron transport chain; CIII, complex III in mitochondrial electron transport chain; CYP, cytochrome P450 monooxygenase; ERO1, ER oxidoreductin 1; FOXO, forkhead box transcription factor; NOX, NADPH oxidase; PDI, protein disulfide isomerase; PMK-1, p38 mitogen-activated protein kinase; PRX, peroxiredoxin; Rph1p, H3K36 demethylase (yeast); SET1, H3K4 methyltransferase; SKN-1, C. elegans functional ortholog of the mammalian Nrf2 transcription factor; SOD, superoxide dismutase.

Figure 4

The complex relationship between ROS and lifespan. ROS are beneficial as mediators of redox signaling and their moderate production in model organisms can extend lifespan depending on the timing, site, levels, and species. ROS, reactive oxygen species.